Journal Club
December 2nd, 2009
Elizabeth Perry, PharmD
Connolly SJ, Ezekowitz MD, Phil CB, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM.
2009;361(12):1139-51.
Background
 Atrial fibrillation affects 2.3 million Americans and can increase the risk of stroke 5-fold
 Vitamin K antagonist, warfarin, is the currently the only available oral option for long term anticoagulation to
reduce the risk of stroke
 Warfarin is burdensome to use due to multiple drug-drug and drug-food interactions and the need for frequent
monitoring leading to high discontinuation rates
o Only about 51% of people with Afib qualify for warfarin use and less the half of people taking warfarin are
in the therapeutic range
 Dabigatran is an oral direct thrombin inhibitor being tested as an alternative to warfarin for patients needing long
term anticoagulation for primary and secondary VTE prevention, stroke prevention, and ACS
 Dabigatran is a prodrug that when converted to its active metabolite specifically targets thrombin, the key enzyme
responsible for converting fibrinogen to fibrin in the clotting pathway
o Dabigatran has a rapid onset of action (within 2 hours), a long half life (14-17 hrs), is not metabolized by
the CYP450 system, is 80% renally eliminated
o Dabigatran has a low potential for drug-drug interactions and no significant drug-food interactions
o Dabigatran does not require monitoring
Study Objective
 To compare the safety and efficacy of dabigatran at two doses, 110 mg twice daily or 150 mg twice daily, to
warfarin in prevention of stroke in patients with atrial fibrillation
 To compare the risk of bleeding and hemorrhagic stroke between warfarin and dabigatran
Study Design
 Randomized, partially-blinded, noninferiority trial
 Patients randomized to dabigatran in a blinded fashion while warfarin was administered open-label and adjusted
based on INR
 Multicenter and international – 951 centers in 44 countries
Methods
 Number of patients enrolled: 18,113
 Inclusion criteria:
o Documented atrial fibrillation by EKG at screening or within previous 6 months, and one of the following
characteristics (CHADS criteria): previous stroke of TIA, LVEF <40%, NYHA class II or higher heart failure
symptoms within 6 months prior to screening, ≥ 75 years of age, or 65-74 years with diabetes mellitus,
hypertension, or coronary artery disease
 Exclusion criteria:
o Severe heart valve disorder, stroke within 14 days, or severe stroke within 6 months before screening, a
condition that increased the risk of hemorrhage, CLcr < 30 ml/min, active liver disease, pregnancy
 Treatment options
o Dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin adjusted to INR 2-3
 Outcomes
o Primary efficacy outcome: Stroke (ischemic, hemorrhagic, or unspecified) or systemic embolism during
follow-up period
o Primary safety outcome: Major hemorrhage (drop in Hgb by 2 g/dL or transfusion of 2 units blood)
o Secondary outcomes: stroke, systemic embolism, death

o Other outcomes: myocardial infarction, pulmonary embolism, transient ischemic attack, hospitalization
Outcome assessment
o Follow-up visits occurred 14 days after randomization, at 1 and 3 months, and every 3 months thereafter
for the 1st year, and then every 4 months until the study ended
o INR monitoring occurred at least every month
o Systemic embolism documented by imaging, surgery or autopsy
Statistics
 Noninferiority evaluated using Cox proportional hazards modeling
o Upper bound of confidence interval for relative risk compared to warfarin < 1.46
o Higher of 2 p values (for 2 dabigatran doses) < 0.025 for both doses to be declared noninferior
o If one p value > 0.025 then the lower value must be <0.0125 be declared significant
 Intention to treat analysis
 After noninferiority determined then p values reported for superiority
o Cox regression for relative risks
o Chi-square to compare adverse events and discontinuation
 18,000 patients needed to achieve 84% power to evaluate for noninferiority (β=0.16)
Results
 Number of patients in each treatment group:
o Dabigatran 110 mg BID = 6015 patients
o Dabigatran 150 mg BID = 6076 patients
o Warfarin (adjusted to INR 2-3) = 6022 patients
 Patients were similar at baseline with average age of 71 years, 63.6% men, and average CHADS score=2.1
 Follow-up:
o Median duration of follow-up: 2 years
o Lost to follow-up: 20 patients
o Discontinuation rate at 2 years: 20.7% for dabigatran 110 mg BID, 21.2% for dabigatran 150 mg BID, and
16.6% for warfarin
o INR within therapeutic range for 64% of follow-up period in warfarin treated patients
 Outcomes
o Stroke or systemic embolism (primary outcome):
 Dabigatran 110 mg BID – 182 patients (1.53% per yr)
 Noninferiority - P<0.001
 Superiority - RR=0.91 (CI 0.74-1.11, P=0.34)
 Dabigatran 150 mg BID – 134 patients (1.11% per yr)
 Noninferiority - P<0.001
 Superiority - RR=0.66 (CI 0.53-0.82, P<0.001)
 Warfarin – 199 patients (1.69% per yr)
o Hemorrhagic stroke
 Dabigatran 110 mg BID = 0.12% per year (P<0.001)
 Dabigatran 150 mg BID = 0.1% per year (P<0.001)
 Warfarin = 0.38% per year
o Myocardial Infarction
 Dabigatran 110 mg BID = 0.72% per year (P=0.07)
 Dabigatran 150 mg BID = 0.74% per year (P=0.048)
 Warfarin = 0.53% per year
o No significant impact on death from any cause
o Major bleeding
 Dabigatran 110 mg BID = 2.71% per year (P=0.003)
 Dabigatran 150 mg BID = 3.11% per year (P=0.31)
 Warfarin = 3.36% per year
o
o
o
Rates of life threatening bleeds, intracranial bleeding, and major and minor bleeds were all significantly
higher for warfarin treated patients
 Except for major gastrointestinal bleeds which was significantly higher in the dabigatran 150 mg
BID treatment group (p<0.001)
Comparison between the 2 dabigatran doses
 Stroke and systemic embolism – dabigatran 150 mg BID significantly reduced risk (P<0.005)
 Bleeding – dabigatran 150 mg BID with trend toward increased risk of major bleeding (P=0.052),
increased risk of GI bleed (p<0.001), and minor bleeding (p<0.001)
Adverse events
 Dyspepsia
 Warfarin (5.8%), dabigatran 110 mg BID (11.8%), dabigatran 150 mg BID (11.3%)
 No significant difference in liver function assessment
Conclusions
 Either dose of dabigatran may be considered a safe and effective oral alternative to warfarin for prevention of
stroke in patients with atrial fibrillation and high risk of stroke (based on CHADS score), while the lower dose will
reduce bleeding risk it does not provide significant advantage with regard to stroke prevention, the higher dose
does provide a treatment advantage but with similar risks of bleeding and higher risk of GI bleed and myocardial
infarction compared to warfarin
 Both doses offer the benefit of improved patient quality of life by reducing the number of monitoring
appointments and lifestyle restrictions
 Potentially offers access to anticoagulation to people who may have been ineligible for warfarin due to
contraindications or inability to follow-up
 No other oral agent to date has been identified that is as effective as warfarin without unacceptable toxicities
 Significant cost differences in the two drugs may be offset by the reduction in the number of clinic visits, travel
expenses, etc.
 Other evidence with dabigatran:
o Primary VTE prevention following hip and knee replacement (RENOVATE, REMODEL, REMOBILIZE)
 RENOVATE – randomized, double-blind, multicenter, noninferiority trial comparing dabigatran
150 mg or 220 mg daily to enoxaparin 40 mg SQ daily for VTE prevention after total hip
replacement; both doses of dabigatran found to be noninferior to enoxaparin in preventing
symptomatic and venographic DVT, PE, and all-cause mortality with no significant difference in
rates of major bleeding or adverse events
 REMODEL - randomized, double-blind, multicenter, noninferiority trial comparing dabigatran 150
mg or 220 mg daily to enoxaparin 40 mg SQ daily for VTE prevention after total knee
replacement; both doses of dabigatran found to be noninferior (but not superior) to enoxaparin
in preventing symptomatic and venographic DVT, PE, and all-cause mortality with no significant
difference in rates of major bleeding or adverse events
o Acute VTE treatment (RECOVER): dabigatran 150mg BID vs. warfarin (after heparin bridge)
o Secondary VTE prevention (REMEDY and RESONATE): dabigatran 150 mg BID vs. warfarin
o Secondary ACS prevention (REDEEM): dose finding for dabigatran (4 doses) + clopidogrel and aspirin or
placebo + clopidogrel and aspirin
Limitations
 Designed to assess noninferiority, not superiority (questionable superiority reported for high dose dabigatran)
 Unblinded for warfarin – potential for bias (unavoidable)
 Concomitant use of aspirin and other anticoagulants was permitted and not compared between groups
 Higher discontinuation rate with both doses of dabigatran with majority of discontinuation due to “patient
decision”, no report of what led to that decision
RE-VOLUTIO